Project Description

Summary

Epithelial ovarian cancer (EOC) is the most lethal gyncaecological malignancy causing 41900 deaths annually in Europe. The predominance of aggressive Type II tumours (mainly high-grade serous histology), which are characterised by a high frequency of p53 mutations, and primary or acquired resistance to platinum-based chemotherapy profoundly contribute to the high mortality rate. With current standard therapy the median overall survival of metastatic platinum-resistant ovarian cancer patients is only 14 month.

There is a pressing need for more effective, innovative treatment strategies to particularly improve survival in this subgroup of epithelial ovarian cancer patients. The GANNET53 trial aims to achieve this goal by applying a highly innovative concept that has grown from solid basic research findings made by members of the GANNET53 consortium.

This is a drug strategy targeting a central driver of tumour aggressiveness and metastatic ability, namely mutant p53, via an innovative new Hsp90 (heat shock protein 90) inhibition mechanism. The most advanced, second-generation Hsp90 inhibitor is used, Ganetespib. The first part (Phase I) of the GANNET53 trial will test the safety of Ganetespib in a new combination with standard chemotherapy (Paclitaxel weekly) in high-grade serous, high-grade endometrioid or undifferenciated, platinum-resistant ovarian cancer patients. The second part (randomised Phase II) will examine the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone in this group of ovarian cancer patients.

We established a highly efficient consortium with previously proven capability and manpower to perform this multicentre clinical trial and assess our innovative therapeutic concept in this deadly disease. Our consortium consists of national clinical trial groups in gynaecological oncology and high-volume university centres as well as noted p53 scientists and 3 innovative small and medium sized companies (SMEs). Since ovarian cancer is defined as a rare cancer a scale at the European level is crucial for the planned clinical trial.

General Objectives

The GANNET53 trial combats metastatic platinum-resistant ovarian cancer with a novel drug strategy that targets the central driver of aggressiveness and metastatic ability of these epithelial ovarian cancers, namely stabilised mutant p53 protein, for degradation via an innovative Hsp90 (heat shock protein 90) inhibition mechanism in order to substantially improve SURVIVAL.

Rationale

Recent data from the EUROCARE database showed an age-standardised 5-year overall survival rate of EOC patients of only 36.1% (95% CI 35.4–36.8; Oberaigner et al., Acta Oncol 51:441-53, 2012).

About 66,700 women are diagnosed with ovarian cancer European-wide and 41,900 die of this disease every year.

This high mortality rate is due to the predominance of late-stage diagnoses, a high relapse rate after primary therapy and poor response of metastatic platinum-resistant tumours to salvage regimens. About 70% of EOC patients present with metastasised disease at time of primary diagnosis (peritoneal carcinosis). The current standard of primary therapy is cytoreductive surgery and adjuvant platinum-based chemotherapy. The addition of bevacizumab has recently been shown to improved progression-free survival in women with ovarian cancer (Perren et al., N Engl J Med 365:2484-96, 2011). Initial response rates are high, but inevitably the vast majority of patients will relapse in short time and ultimately die of the disease.

A major treatment obstacle is the fact that 25-30% of patients are resistant to first-line platinum-based chemotherapy. By definition, they experience progressive or persistent disease during initial platinum-based therapy (primary platinum-refractory), or relapse of disease after less than 6 months after completion of first-line platinum-based therapy (primary platinum-resistant). Eventually most patients will become resistant to platinum after reiterative therapy with platinum-based regimens (secondary platinum-resistant disease). Treatment options are limited for platinum-resistant patients. There is general consensus that surgery is only indicated in selected cases, where palliation of symptoms has priority (Schorgeet al., Oncology 25:928-34, 2011). No “standard” chemotherapy is currently available and systemic treatment is highly dependent on the physician’s choice. A number of cytotoxic agents including non-pegylated or pegylated liposomal Doxorubicin (PLD), Topotecan, Gemcitabine and alkylating agents such as Treosulphan or Cyclophosphamide have shown a relative modest antitumour activity as single agent. This is reflected by low response rates < 20% for each agent and only short lasting remissions (Mutch et al, J Clin Oncol 25:2811-8, 2007; Gordon et al, J Clin Oncol 19:3312-22, 2001). However, Paclitaxel given as single agent on a weekly basis at a dose of 80-90 mg/m2/week, proved to be one of the most effective regimens in the platinum-resistant situation, with response rates in the range of 20-60% (Lortholary et al, Ann Oncol 23:346-52, 2012; Richard et al., Nature Reviews Clinical Oncology 7:575-82, 2010). This efficacy is even seen in cases that exhibit resistance to paclitaxel administered via an ‘every-3-week’ schedule. It is noteworthy that the weekly schedule is by far less toxic. However, the progression-free interval may be short.

Data from clinicopathological and molecular studies performed to date led to a model in which EOC can be divided into two broad categories, designated type I and type II tumours (Shih and Kurman, Am J Pathol 164:1511-8, 2004). In this model, type I and type II refer to critical molecular tumourigenic pathways and not to specific histopathological patterns.

Type II tumours are highly aggressive. They evolve rapidly, have a high metastatic activity and therefore have almost always already spread beyond the ovaries at primary diagnosis. Thus, this tumour type is the most problematic from a clinical point of view. Moreover, type II tumours account for the overwhelming majority (>70%) of EOC. Histologically, type II tumours are mainly high-grade serous (HGS) carcinomas, and the remainder are high-grade endometrioid, undifferentiated carcinomas or a subset of clear cell carcinomas. HGS carcinoma accounts for ~ 85 % of all ovarian cancer deaths.

Importantly, type II tumours are characterised by the near ubiquitous presence of p53 mutations - their preeminent molecular hallmark, which in contrast are very rare in type I tumours. This strongly suggests that mutp53 is a central oncogenic driver in the pathogenesis of these tumours. Ahmed et al (J Pathol 221:49-56, 2010) sequenced exons 2-11 and intron-exon boundaries in DNA from 145 patients with HGS tumours and identified p53 mutations in 96.7% of cases. Also, the Cancer Genome Atlas Research Network (TCGA) completed whole-exome sequencing on an unprecedented 316 cases of HGS tumours and established that p53 mutations are present in > 96 % (Nature 474:609-1512, 2011).

In sharp contrast, type I tumours almost always lack p53 mutations, but often harbour somatic mutations of protein kinase genes including PIK3CA and ERRB2, and other signalling molecules including KRAS, BRAF, CTNNB1 and PTEN (Wu et al, Cancer Cell 11:321-33.13, 2007). Type I tumours are slow-growing, often confined to the ovary at diagnosis, and develop in a stepwise fashion from well-recognised precursors, in most cases borderline tumours. Type I tumours include low-grade serous carcinomas, low-grade endometrioid carcinomas, mucinous carcinoma and a subset of clear cell carcinomas.

Based on the fact that type II tumours are the most lethal and the most prevalent EOC type and that mutp53 is the central oncogenic driver in these tumours, we will apply our novel therapeutic approach in a stratified molecularly-defined patient population with high-grade serous, high-grade endometrioid and undifferentiated EOC. This offers the highest potential for achieving the most profound survival benefit.

Scientific background

Alterations in the p53 tumour suppressor gene, often called the Guardian of the Genome (citing Sir David Lane, co-discoverer of p53 in 1979, and member of our External Advisory Board) are the most common genetic alterations in human cancers. p53 mutations occur in >50% of all human cancers. In sharp contrast to all other tumor suppressor genes, which typically lose protein expression upon mutation, 85% of p53 mutations are missense mutations in the DNA-binding domain, and they frequently generate conformationally aberrant proteins (full-length ‘mutp53’). For the longest time, mutant p53 (mutp53) protein was considered a 'dead' protein that has lost its potent tumor suppressor function (Brown et al, Nat Rev Cancer 9:862-73, 2009; Vaseva and Moll, Biochem Biophys Acta 1787:414-20, 2009), and was just lying around as waste in the tumor cell. Recently however, new insights changed this concept and established that mutp53 acquires broad new oncogenic activity (gain-of function, GOF).

Compelling new evidence from mutp53 knock-in (KI) mice carrying human hotspot mutations provide definitive genetic proof for GOF in vivo (Olive et al, Cell 119:847–60, 2004; Lang et al, Cell 119:861–72, 2004; Hanel et al, Cell Death & Diff 20:898-909, 2013): The knock-in mice show a broader tumour spectrum including adenocarcinomas, higher tumour bulk, grade and invasion, multiple tumour types per mouse, and newly gained metastatic ability compared to the traditionally used p53 null mice (knock-out) that mainly get T-lymphomas and never metastasise.

  • Constitutive stabilisation is the hallmark of (full-length missense) mutp53 proteins in tumour cells and their aberrant accumulation is the prerequisite for exerting GOF. Most importantly, mutp53 cancers develop a strong dependency on high levels of mutp53 for survival (‘addiction’ to mutp53). This was recently proven with KI mice.
  • As a consequence, acute withdrawal of mutp53 triggers strong spontaneous cytotoxicity, blocking invasion and metastasis and restoring chemotherapy-induced cell death in human cancer xenografts in vivo (Muller et al, Cell 139:1327–41, 2009; Li et al, Mol Canc Res 9:577–88, 2011; Bossi et al, Oncogene 25:304-9, 2006; Yan et al, Canc Res 68:6789-96, 200817-20).

Due to their aberrant conformation mutp53 proteins depend on permanent folding support by the multi-component Hsp90 chaperone machinery (which in turn is constitutively activated in tumour but not in normal cells), and it is this stable interaction between mutp53 and Hsp90 that is largely responsible for mutp53 accumulation specifically in tumour cells (Figure 1; Li et al, Mol Cancer Res 9:577–88, 2011; Li et al, Cell Death & Diff 18:1904-13, 2011).

Pharmacological inhibition of the machine’s core ATPase Hsp90 (such as by the highly potent second generation Hsp90 inhibitor Ganetespib) destroys the complex between Hsp90 and mutp53, thereby liberating mutp53 and inducing its degradation by MDM2 and CHIP E3 ubiquitin ligases. As a consequence, Hsp90 blockade shows preferential and strong cytotoxicity for mutp53 cancer cells in culture and in xenografts. In contrast, wtp53 or nullp53 cells show only minimal responses. Moreover, Hsp90 blockade - by virtue of depleting mutp53 - dramatically sensitises mutp53 cancer cells to chemotherapeutics. Thus, Hsp90 inhibition mediates effective destabilisation and degradation of mutp53 in human tumour cells, acutely withdrawing an oncoprotein these cells depend on for survival. This is strongly cytotoxic in mutp53 harbouring tumour cells. Given the advanced development of Hsp90 inhibitors, this new paradigm holds immediate strong translational potential for significantly improving outcome in mutp53-driven cancers such as type II EOC.

Figure: Scientific principle of the GANNET53 trial (Li et al, Cell Death & Diff 18:1904-13, 2011; Li et al, Mol Cancer Res 9:577–88, 2011).
Destabilisation of mutant p53 protein by inhibition of the Hsp90 chaperone causes subsequent degradation by MDM2 or CHIP E3 ligases: Stable complex formation with Hsp90 causes aberrant stabilisation of mutp53 in cancer cells. MDM2 and CHIP, which in principle are capable of degrading mutp53, are unable to degrade mutp53 as long as it is protected by the complex (‘caging’). Stabilised mutp53 exerts oncogenic gain-of-function (GOF). Acute depletion of mutp53 in tumour cells is strongly cytotoxic in all tested mutp53 solid cancer cell types tested (ovarian, breast, colon, and prostate). Small molecule inhibitors of the Hsp90 ATPase (such as the highly potent second generation Hsp90inhibitor Ganetespib, or the weaker first generation 17AAG + SAHA) acutely deplete mutp53, which is strongly cytotoxic in mutp53 harbouring tumour cells.

The test drug Ganetespib

The GANNET53 trial applies the safest, most effective and clinically most advanced Hsp90 (heat shock protein 90) inhibitor available.

Ganetespib is a highly potent, 2nd generation Hsp90 inhibitor (synthetic small molecule) developed by Synta Pharmaceuticals Corp. (Lexington, MA, USA). Synta agreed to provide the drug for this entire trial at no charge.

Ganetespib has been studied in 5 completed Synta-sponsored clinical trials (studies 9090-02, 9090-03, 9090-04, 9090-05, and 9090-07) and 3 completed Synta-sponsored studies in normal healthy volunteers (9090-12, 9090-13, and 9090-15). Ganetespib is being studied in 6 ongoing Synta-sponsored clinical trials. Studies include: one phase I study, three phase II studies, one phase IIb study, and one phase III study. Ganetespib is also being studied in 17 investigator-sponsored clinical trials (ISTs), 8 of which are currently enrolling patients. The majority of ISTs are proof-of-concept studies across a variety of tumour types as well as haematologic malignancies. The ISTs currently enrolling include: two phase I/II studies, two phase I studies, and four phase II studies. Please refer to http://clinicaltrials.gov for further information.